Role of cyclin-dependent kinase 4/6 inhibitors in the current and future eras of cancer treatment.

Cyclin-dependent kinase 4/6 inhibitors, which act by inhibiting progression from the G1 to S phases of the cell cycle, include palbociclib, ribociclib, abemaciclib, and trilaciclib. Palbociclib and ribociclib are currently food and drug administration-approved for use in combination with aromatase inhibitors in postmenopausal women with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Palbociclib is also food and drug administration-approved for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Abemaciclib is the newest cyclin-dependent kinase 4/6 inhibitor to gain Food and Drug Administration (FDA) approval, specifically as monotherapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer previously treated with chemotherapy and endocrine therapy. Abemaciclib also shares a similar indication with palbociclib for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Trilaciclib use remains largely investigational at this time. However, despite FDA-approval for only metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, all four cyclin-dependent kinase 4/6 inhibitors have shown promise in hematologic malignancies and non-breast solid tumors. Although further research is needed, cyclin-dependent kinase 4/6 inhibitors represent intriguing developments in the treatment of various malignancies, including those with such poor prognoses as glioblastoma multiforme, mantle cell lymphoma, and metastatic melanoma. We discuss the approved indications, current research, and areas of future exploration for palbociclib, ribociclib, abemaciclib, and trilaciclib.

Laparoscopic sleeve gastrectomy improves renal transplant candidacy and posttransplant outcomes in morbidly obese patients.

Morbid obesity is a barrier to kidney transplantation due to inferior outcomes, including higher rates of new-onset diabetes after transplantation (NODAT), delayed graft function (DGF), and graft failure. Laparoscopic sleeve gastrectomy (LSG) increases transplant eligibility by reducing BMI in kidney transplant candidates, but the effect of surgical weight loss on posttransplantation outcomes is unknown. Reviewing single-center medical records, we identified all patients who underwent LSG before kidney transplantation from 2011-2016 (n = 20). Post-LSG kidney recipients were compared with similar-BMI recipients who did not undergo LSG, using 2:1 direct matching for patient factors. McNemar's test and signed-rank test were used to compare groups. Among post-LSG patients, mean BMI ± standard deviation (SD) was 41.5 ± 4.4 kg/m2 at initial encounter, which decreased to 32.3 ± 2.9 kg/m2 prior to transplantation (P < .01). No complications, readmissions, or mortality occurred following LSG. After transplantation, one patient (5%) experienced DGF, and no patients experienced NODAT. Allograft and patient survival at 1-year posttransplantation was 100%. Compared with non-LSG patients, post-LSG recipients had lower rates of DGF (5% vs 20%) and renal dysfunction-related readmissions (10% vs 27.5%) (P < .05 each). Perioperative complications, allograft survival, and patient survival were similar between groups. These data suggest that morbidly obese patients with end-stage renal disease who undergo LSG to improve transplant candidacy, achieve excellent posttransplantation outcomes.

Evidence-based Update of Pediatric Dental Restorative Procedures: Preventive Strategies.

BACKGROUND: There has been significant advances in the understanding of preventive restorative procedures regarding the advantages and disadvantages for restorative procedures; the evidence for conservative techniques for deep carious lesions; the effectiveness of pit and fissure sealants; and the evidence for use of resin infiltration techniques. AIM: The intent of this review is to help practitioners use evidence to make decisions regarding preventive restorative dentistry in children and young adolescents. STUDY DESIGN: This evidence-based review appraises the literature, primarily between the years 1995-2013, on preventive restorative strategies. The evidence was graded as to strong evidence, evidence in favor, or expert opinion by consensus of authors Results: The preventive strategy for dental caries includes individualized assessment of disease progression and management with appropriate preventive and restorative therapy. There is strong evidence that restoration of teeth with incomplete caries excavation results in fewer signs and symptoms of pulpal disease than complete excavation. There is strong evidence that sealants should be placed on pit and fissure surfaces judged to be at risk for dental caries, and surfaces that already exhibit incipient, non-cavitated carious lesions. There is evidence in favor for resin infiltration to improve the clinical appearance of white spot lesions. CONCLUSIONS: Substantial evidence exists in the literature regarding the value of preventive dental restorative procedures.

Evidence-based Update of Pediatric Dental Restorative Procedures: Dental Materials.

BACKGROUND: The science of dental materials and restorative care in children and adolescent is constantly evolving, and the ongoing search for ideal restorative materials has led to plethora of research. AIM: To provide an evidence base to assist dental practitioners choose appropriate restorative care for children and adolescents. STUDY DESIGN: This evidence-based review appraises this literature, primarily between the years 1995-2013, for efficacy of dental amalgam, composites, glass ionomer cements, compomers, preformed metal crowns and anterior esthetic restorations. The assessment of evidence for each dental material was based on a strong evidence, evidence in favor, expert opinion, and evidence against by consensus of the authors. RESULTS: There is varying level of evidence for the use of restorative materials like amalgam, composites, glass ionomers, resin-modified glass-ionomers, compomers, stainless steel crowns and anterior crowns for both primary and permanent teeth. CONCLUSIONS: A substantial amount data is available on restorative materials used in pediatric dentistry; however, there exists substantial evidence from systematic reviews and randomized clinical trials and clinicians need to examine and understand the available literature evidence carefully to aid them in clinical decision making.

The use of botulinum toxin in otorhinolaryngology: an updated review.

BACKGROUND: The use of botulinum toxin in Otorhinolaryngology has rapidly expanded over the last decade. Current observation is that the use of botulinum toxin in Otorhinolaryngology is relatively poorly acknowledged by Otorhinolaryngologists. OBJECTIVE OF REVIEW: To summarise the non-cosmetic uses of botulinum toxin in Otorhinolaryngology. TYPE OF REVIEW: Narrative. SEARCH STRATEGY AND EVALUATION METHOD: A literature search was performed using the Medline and Embase databases. Combinations of 'botulinum toxin' with each indication were searched. A citation was included if it evaluated a non-cosmetic use of botulinum toxin in Otorhinolaryngology. Eligibility of studies was assessed by two reviewers. A total of 1187 abstracts were reviewed and 97 articles identified. CONCLUSIONS: Botulinum toxin provides an effective and minimally invasive treatment option in a wide range of non-cosmetic indications. Side-effects are few and transient with an excellent safety profile. Ongoing research is required to fully critically appraise its uses.

Tubeless field anaesthesia for surgical removal of an aspirated endoscopy capsule.

Capsule endoscopy is a safe, minimally invasive procedure used to investigate gastrointestinal bleeding of unknown origin that persists or recurs after a negative initial endoscopy. The most common adverse effects of capsule endoscopy include abdominal pain, nausea and vomiting. Capsule pulmonary aspiration, although a rare complication, has been reported in the literature. Most reported cases resolve without further medical intervention. In these cases, the capsule is either expelled by coughing, or it re-enters the oropharynx and is then swallowed. In a small number of cases, the capsule remains in the lung, unable to be expectorated. This requires prompt diagnosis and emergency bronchoscopic removal under general anaesthesia. Due to the smooth, rounded surfaces of the capsule, it may be difficult to grasp, and consequently extraction may be technically challenging. The existing literature contains limited documentation on anaesthetic and surgical approaches for managing an aspirated endoscopy capsule. In this case report, we present the management of an aspirated endoscopy capsule in a district general hospital, in which thoracic surgery was not available. Local resources were used to manage this potentially life-threatening complication without patient transfer. In our case, we provided a tubeless field to optimise surgical access. This facilitated the successful surgical extraction of the endoscopy capsule from the left main bronchus.

Transnational caregiving: Part 1, caring for family relations across nations.

This article concerns how globalization and the aging of the world's population are affecting the already complex issue of intergenerational transnational caregiving. Globalization has caused an increase in workforce mobility with large numbers of individuals seeking employment overseas. This, coupled with increased longevity globally, has resulted in many workers leaving their elderly parents in need of care in their home countries. This has spawned caregiving across national borders, or caring for family relations across nations. Currently in the United States, not enough emphasis is given to family caregiving. Data compiled by AARP and the National Alliance for Caregiving estimate the economic value for this group of family caregivers in 2007 to be $375 billion, accounting for 34-52 million family caregivers per given year. This does not include those families who are transnational caregivers. The seminal work in this emerging field has been done by social anthropologists Loretta Baldassar, Cora Velekoop Baldock, and Raelene Wilding, who have defined the components of transnational caregiving based on an ethnographic study using qualitative data to study nine immigrant communities in Western Australia. Although their research focused on caregiving from a distance, additional work has been added to the discussion by introducing the element of "care drain" and further cultural perspectives. Therefore, this research is an exploratory study on intergenerational transnational caregiving within the context of the changing world and its demographics. Within the context of globalization and global aging, the following questions are addressed: What is the significance of family caregiving? What is a transnational? How has technology changed "transnationalism" today? What are the elements that comprise transnational caregiving? How does culture play a role in transnational caregiving? What are some of the national initiatives undertaken by governments to aid in workforce issues and recognition of caregiving organizations? By exploring these questions, it is hoped that there will be a better understanding of transnational caregiving and its relevance in all societies.

Interleukin 10: a novel stimulatory factor for mast cells and their progenitors.

We have characterized the mast cell stimulating activity of murine cytokine synthesis inhibitory factor, referred to as interleukin 10 (IL-10). It was found that IL-10 alone failed to support the growth of mast cell lines and mast cell progenitors. Nevertheless, it dramatically enhanced their growth when combined with IL-3 or IL-4. Moreover, IL-4 plus IL-10 supported the proliferation of mast cells as well as IL-3, suggesting that these two factors may provide a pathway for their development independent of IL-3. However, optimal mast cell growth was stimulated by the combination of IL-10, IL-4, and IL-3. This particular set of cytokines are coordinately produced by activated T cells and may constitute an effective network regulating early and late stages of mast cell development during certain immune responses.

Antianxiety activity of Gelsemium sempervirens.

CONTEXT: The clinical applications of well-known benzodiazepines as anxiolytic agents are limited because of their side effects. Therefore, the development of new pharmacological agents, from medicinal plants, is well justified. OBJECTIVE: Among medicinal plants, Gelsemium sempervirens (L.) Aiton. (Loganiaceae) has been recommended for relief of anxiety in traditional folk medicines. Nevertheless, no pharmacological studies have so far evaluated it in this regard. The purpose of the present study was to investigate the anxiolytic effects of various extracts of the roots and rhizomes of G. sempervirens. MATERIALS AND METHODS: Petroleum ether, chloroform, methanol, and water extracts of G. sempervirens were prepared by successive extractions using a Soxhlet apparatus, and subsequently evaluated for antianxiety activity using the elevated plus maze model. Diazepam was used as standard drug. RESULTS: Among various extracts, the methanol extract of G. sempervirens exhibited significant increases in open arm entries and mean time spent in open arms at the dosage of 150 mg/kg. A fraction (F9.4) derived from the methanol extract was also observed to exhibit significant anxiolytic activity at the dose level of 10 mg/kg in the elevated plus maze test. CONCLUSION: The present study clearly demonstrated that the methanol extract exerts an anxiolytic effect on mice, and it could serve as a new approach for the treatment of anxiety.

Comparison of sprinting vs non-sprinting to wean nasal continuous positive airway pressure off in very preterm infants.

OBJECTIVE: Though nasal continuous positive airway pressure (NCPAP) is commonly used for non-invasive neonatal respiratory support, the optimal method of weaning NCPAP is not established. In this prospective, two-center randomized control trial we hypothesize that gradually increasing spontaneous breathing time off NCPAP increases successful weaning from NCPAP in infants born <31 weeks gestational age. STUDY DESIGN: Infants were randomized to one of the two NCPAP weaning protocols, a sprinting, that is, gradually increasing spontaneous breathing time off CPAP, protocol vs a non-sprinting (weaning pressure down) protocol. RESULT: Eighty-six infants were enrolled in one of the two study groups. Thirty-one infants (77%) in the sprinting group and 30 (75%) in the non-sprinting group were successfully weaned off NCPAP at the first attempt (P>0.05). It took 1.3 (1 to 1.75) (median (IQR)) attempts and 7 (7 to 7) days to wean NCPAP off in the sprinting group vs 1.3 (1 to 1.75) attempts and 7 (7 to 10) days in the non-sprinting group (P>0.05). Additionally, no differences in the secondary outcomes of bronchopulmonary dysplasia, severe retinopathy of prematurity (⩾stage 3), periventricular leukomalacia and length of stay were noted between the two groups. CONCLUSION: Weaning NCPAP via sprinting or non-sprinting protocol is comparable, not only for successful weaning but also for the occurrence of common neonatal morbidities that impact the long-term outcome in premature infants (ClinicalTrials.gov number, NCT02819050).

Ensuring patient safety when implementing a new diagnostic pathway for thyroid nodules.

Introduction The aim of this study was to determine whether ultrasound alone is sufficient to safely exclude malignancy in thyroid nodules in a district general hospital setting, to comply with the latest British Thyroid Association guidelines. Methods This retrospective study investigated the quality of ultrasound reporting and the correlation between ultrasound report and histology for individual thyroid nodules. Cases were selected from the thyroid multidisciplinary meeting and included all patients having undergone surgery for a thyroid malignancy in a one-year period. Results Forty-seven patients were included in the study. Ultrasound reports were reviewed and assessed, in which 21 clinicians were involved; 36% of scans included a summary of whether the nodule(s) overall appeared benign, equivocal, suspicious or malignant; 4% of reports included a U classification; 81% of reports commented on cervical lymph nodes. Ultrasound was compared with histology. The sensitivity of ultrasound in correctly identifying nodules requiring further investigation was of 56% and specificity was 81%. Positive predictive value was 81% and negative predictive value was 56%. Discussion These findings suggest that, in a district general hospital setting without a dedicated head and neck radiologist, using only ultrasound and limiting fine-needle aspiration cytology to identify suspicious nodules may not be safe, as a high number of nodules appearing benign on ultrasound may ultimately prove to be malignant.

Role of EBNA-1 in arresting replication forks at the Epstein-Barr virus oriP family of tandem repeats.

The 20-member family of 30-bp tandem repeats located within the oriP region of Epstein-Barr virus (EBV) can act as a transcriptional enhancer in the presence of EBV nuclear antigen 1 (EBNA-1). A replication fork barrier and a termination site of plasmid replication in human B cells is also found within or near the EBV tandem repeats. Within each tandem repeat is a consensus binding sequence for the EBNA-1 protein that is required for extrachromosomal maintenance of oriP-containing plasmids. To investigate the factors that contribute to the arrest of replication forks and termination in the region of the family of repeats, we have used an in vitro replication system in which replication of EBV recombinant plasmids is initiated from the simian virus 40 (SV40) DNA replication origin in the presence of SV40 T antigen and soluble extracts prepared from human cells. The system can support bidirectional replication, initiating from the SV40 DNA origin with termination occurring in a region opposite the origin. Using two-dimensional agarose gel electrophoresis, we observed a barrier to replication forks in the presence of EBNA-1 in the region of the EBV repeats. Termination occurs at or near the tandem repeats in a manner similar to that observed in vivo (T.A. Gahn and C.L. Schildkraut, Cell 58:527-535, 1989). Reducing the number of repeats from 20 to 6 had little effect on the strength of the replication fork barrier. In the absence of EBNA-1, replication forks also arrested at the EBV repeats, but at a much lower efficiency. The addition of competitor DNA containing the EBV family of repeats can almost completely abolish the replication barrier produced in the presence of EBNA-1.

The coordinate replication of the human beta-globin gene domain reflects its transcriptional activity and nuclease hypersensitivity.

The temporal order of replication of DNA sequences in the chromosomal domain containing the human beta-globin gene cluster and its flanking sequences (140 kilobases) was measured and compared in two different human cell lines. In human erythroleukemia (K562) cells, in which embryonic and fetal globin genes are transcribed, all of the sequences we examined from the beta-globin domain replicated early during S phase, while in HeLa cells, in which globin genes are transcriptionally silent, these sequences replicated late during S. Potential sites of initiation of DNA replication within this domain were identified. The beta-globin gene domain was also found to differ with respect to the nuclease sensitivity of the chromatin in these two cell lines. In K562 cells, hypersensitive sites for endogenous nucleases and DNase I were present in the chromatin near the earliest-replicating segments in the beta-globin domain.

Transcription of mouse rDNA and associated formation of the nucleolus organizer region after gene transfer and amplification in Chinese hamster cells.

Mouse rDNA can initiate transcription by using only Chinese hamster cell components, and this is associated with nucleolus organizer activity. To demonstrate this, we transferred a 3.2-kilobase segment of mouse rDNA containing the promoter, the transcription initiation site, and part of the external transcribed spacer to dihydrofolate reductase-deficient Chinese hamster cells by cotransformation with an abbreviated mouse dhfr gene. Stepwise selection for methotrexate resistance produced sublines in which the mouse rDNA was usually coamplified with the donor dhfr DNA and occupied the same site or sites in the hamster genome, as shown by in situ hybridization. Transcription from mouse rDNA was demonstrated in two such lines, and S1 protection mapping indicated faithful initiation of the transcript. In some cells from both lines, the chromosome segments containing amplified mouse rDNA showed multiple silver-staining regions (i.e., active nucleolus organizers). Although the transferred mouse rDNA was able to use the rDNA transcriptional machinery of the Chinese hamster, the level of transcription was much lower than expected from the rDNA copy number, and a large fraction of each amplified region showed no silver staining. Since the absence of silver staining is generally correlated with the absence of transcription, many copies of the amplified mouse rDNA may have been in a chromatin conformation in which they could not be transcribed. This was not associated with the extensive methylation seen in other amplified, inactive rDNA sequences.

Activation and repression of a beta-globin gene in cell hybrids is accompanied by a shift in its temporal replication.

To investigate whether a switch in the transcriptional activity of a gene is associated with a change in the timing of replication during the S phase, we examined the replication timing of the beta-globin genes in two different types of somatic cell hybrids. In mouse hepatoma (Hepa 1a) x mouse erythroleukemia (MEL) hybrid cells, the beta-globin gene from the MEL parent is transcriptionally inactivated and is later replicating than in the parental MEL cell line. In human fibroblast (GM3552) x MEL hybrid cells, the human beta-globin gene is transcriptionally activated, and all of the sequences within the human beta-globin domain (200 kilobases) we have examined appear to be earlier replicating than those in the parental fibroblast cell line. The chromatin configuration of the activated human beta-globin domain in the hybrids is relatively more sensitive to nucleases than that in the fibroblasts. Furthermore, major nuclease-hypersensitive sites that were absent in the chromatin flanking the distal 5' region of the human beta-globin gene cluster in the parental fibroblast cell line are present in the transcriptionally activated domain in the hybrid cell line. These results suggest that timing of replication of globin genes has been altered in these hybrid cells and thus is not fixed during the process of differentiation.

Erythroid-specific nuclease-hypersensitive sites flanking the human beta-globin domain.

Recent evidence suggests that DNA sequences from the region lying 5' of the human epsilon-globin gene are important for erythroid-specific expression of human beta-like globin genes. This region, as well as a region 20 kilobases (kb) downstream from the beta-globin gene, contains a set of developmentally stable, DNase I-superhypersensitive sites that are thought to reflect a chromatin structure supporting active globin gene expression. We have analyzed the chromatin structure in these two regions in a wide variety of nonerythroid and erythroid cells. The study included analysis of chromatin structure changes occurring during globin gene activation in mouse erythroleukemia-human nonerythroid cell hybrids. The results identified a hypersensitive site (III) 14.8 kb upstream of the epsilon-globin gene that was strictly correlated with active globin gene transcription. Interestingly, a multipotent human embryonal carcinoma cell line exhibited a hypersensitive site (IV) 18.4 kb upstream of epsilon-globin that was absent in all other nonerythroid cells examined, suggesting that chromatin structure changes at specific hypersensitive sites during embryonic development may also be important in globin gene repression.

Human ribosomal DNA fragments amplified in hamster cells are transcribed only by RNA polymerase II and are not silver stained.

Cloned human rRNA gene fragments that included the promoter region were introduced into Chinese hamster dihydrofolate reductase-deficient (dhfr-) cells by cotransformation with a dhfr minigene and amplified by selection for methotrexate resistance. The human ribosomal DNA was transcribed by RNA polymerase II, not RNA polymerase I or III. The metaphase chromosome regions containing the transcriptionally active human ribosomal DNA failed to show silver staining.

Replication program of active and inactive multigene families in mammalian cells.

In a comprehensive study, the temporal replication of tissue-specific genes and flanking sequences was compared in nine cell lines exhibiting different tissue-specific functions. Some of the rules we have determined for the replication of these tissue specific genes include the following. (i) Actively transcribed genes usually replicate during the first quarter of the S phase. (ii) Some immunoglobulin genes replicate during the first half of S phase even when no transcriptional activity is detected but appear to replicate even earlier in cell lines where they are transcribed. (iii) Nontranscribed genes can replicate during any interval of S phase. (iv) Multigene families arranged in clusters of 250 kilobases or less define a temporal compartment comprising approximately one-quarter of S phase. While these rules, and others that are discussed, apply to the tissue-specific genes studied here, all tissue-specific genes may not follow this pattern. In addition, housekeeping genes did not follow some of these rules. These results provide the first molecular evidence that the coordinate timing of replication of contiguous sequences within a multigene family is a general property of the mammalian genome. The relationship between replication very early during S phase and the transcriptional activity within a chromosomal domain is discussed.

Prevalence of dental caries and treatment needs in the school-going children of rural areas in Udaipur district.

Dental caries is among the most common dental problems affecting humans. This condition is a major health problem with high prevalence, globally involving the people of all regions and society. This study was conducted on 1587 government school children of Udaipur district in the age group of 5-14 years for recording the prevalence of dental caries and treatment needs. Dental caries was found in 46.75% children, and 76.87% children required some kind of dental treatment.